8GTG

Corticotropin-releasing hormone receptor 1(CRF1R) bound with BMK-I-152 by XFEL

Summary for 8GTG

• Entry DOI: 10.2210/pdb8gtg/pdb
• Descriptor: Isoform CRF-R2 of Corticotropin-releasing factor receptor 1, Endolysin, 8-(4-bromanyl-2,6-dimethoxy-phenyl)-~{N},~{N}-bis(2-methoxyethyl)-2,7-dimethyl-pyrazolo[1,5-a][1,3,5]triazin-4-amine (3 entities in total)
• Functional Keywords: membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 51293.44

Authors

Cho, H.S.,Kim, H. (deposition date: 2022-09-08, release date: 2023-09-13, Last modification date: 2024-11-06)

Primary citation

Kim, H.,Lim, T.,Ha, G.E.,Lee, J.Y.,Kim, J.W.,Chang, N.,Kim, S.H.,Kim, K.H.,Lee, J.,Cho, Y.,Kim, B.W.,Abrahamsson, A.,Kim, S.H.,Kim, H.J.,Park, S.,Lee, S.J.,Park, J.,Cheong, E.,Kim, B.M.,Cho, H.S.
Structure-based drug discovery of a corticotropin-releasing hormone receptor 1 antagonist using an X-ray free-electron laser.
Exp.Mol.Med., 55:2039-2050, 2023

PubMed Abstract: Thus far, attempts to develop drugs that target corticotropin-releasing hormone receptor 1 (CRFR), a drug target in stress-related therapy, have been unsuccessful. Studies have focused on using high-resolution G protein-coupled receptor (GPCR) structures to develop drugs. X-ray free-electron lasers (XFELs), which prevent radiation damage and provide access to high-resolution compositions, have helped accelerate GPCR structural studies. We elucidated the crystal structure of CRFR complexed with a BMK-I-152 antagonist at 2.75 Å using fixed-target serial femtosecond crystallography. The results revealed that two unique hydrogen bonds are present in the hydrogen bond network, the stalk region forms an alpha helix and the hydrophobic network contains an antagonist binding site. We then developed two antagonists-BMK-C203 and BMK-C205-and determined the CRFR/BMK-C203 and CRFR/BMK-C205 complex structures at 2.6 and 2.2 Å, respectively. BMK-C205 exerted significant antidepressant effects in mice and, thus, may be utilized to effectively identify structure-based drugs against CRFR.

PubMed: 37653040
DOI: 10.1038/s12276-023-01082-1

Experimental method

X-RAY DIFFRACTION (2.75 Å)